Zapping Pathological Proteins in Alzheimer’s

AC Immune’s SupraAntigen technology platform is the basis for active and passive immunotherapies against conformation-specific targets.

AC Immune is fighting Alzheimer’s disease on three fronts armed with monoclonal antibodies, vaccines, and small molecules. It is attacking amyloid beta (Abeta) oligomers and tau tangles, the key misfolded proteins involved in the pathological processes of Alzheimer’s.

The body’s immune system does not recognize Abeta or tau as foreign proteins. AC Immune’s immunotherapies trigger the body to make antibodies against these misfolded proteins. “All the antibodies induced attack the pathologic conformation, but do not touch normal healthy proteins,” says Dr. Pfeifer, now CEO.

The company’s SupraAntigen™ technology generates conformation-sensitive antibodies that inactivate all forms of Abeta. Because a single liposome can carry up to 400 antigens on its surface, it has a big, or “supra” impact. The liposomes, made of cholesterol and fatty acids, do not cause inflammation or other immune reactions. Tests show absolutely no antibody response to the inert liposomes in mice or people. “Dosages can be high compared to other drugs,” says Dr. Pfeifer, because “we see hardly any side effects.”

SupraAntigens precisely discriminate against abnormal and normal forms of a protein, and a better safety profile results from this high affinity, says Dr. Pfeifer. The approach does not require T-cell activation, so no brain inflammation or toxicity occurs. “When working in the brain, you need an extremely safe treatment,” she emphasizes.

The SupraAntigen platform makes both mAbs and vaccines. Hundreds of mAbs are generated after injecting a mouse, and ones with the highest affinity and specificity for a target protein are selected for further testing.

The company’s chemical Morphomer™ platform produces small molecule drugs that block the aggregation of Abeta. The Morphomer program grew out of the SupraAntigen platform. “We learned exactly where our liposomes bind and the most effective sites to destroy in sick proteins. We designed small molecules to bind exactly to these sites,” says Dr. Pfeifer. This chemical route proved harder, and it took five years. The lead small molecule, ACI-91, helps to transport Abeta out of the brain and is in Phase II trials.

Prevention Trial

AC Immune exclusively licensed crenezumab, its lead anti-Abeta antibody, to Genentech for clinical development and commercialization. Preclinical studies show that crenezumab binds Abeta and clears it from the brain.

Genentech is testing crenezumab in a trial of cognitively healthy people with a rare genetic mutation that typically triggers Alzheimer’s at around age 45. The mutation affects the gene PSEN1, which is involved in pathways that make Abeta. The trial will determine whether crenezumab can reduce the risk of disease development and slow its progression.

This is the first known prevention trial examining whether an anti-amyloid treatment can stave off Alzheimer’s, claims Dr. Pfeifer. The subjects will be injected with crenezumab or a placebo and then evaluated with brain scans and cognitive tests to monitor signs of early-onset Alzheimer’s. Genentech is collaborating with the NIH, Banner Alzheimer’s Institute, and the University of Antioquia in Colombia.

Current Alzheimer’s therapies are tested in patients who already have mild or moderate symptoms, says Dr. Pfeifer. By the time memory problems occur, many experts believe that too much damage has been done. “We are pleased that an antibody that we discovered is the first drug ever tested in a prevention trial of Alzheimer’s. Promising drugs should be tested years before a person is diagnosed with this terrible disease,” she says.

AC Immune also partnered with Genentech in June 2012 to test another promising mAb that targets tau protein. Like Abeta plaques, tangles of abnormal tau form neurofibrillary tangles, a hallmark of brain lesions in Alzheimer’s patients.

Additional Candidates

In addition to crenuzamab, the therapeutic vaccine ACI-24 is in Phase I/IIa trials. “We have many more candidates waiting to go into the clinic,” says Dr. Pfeifer, including an anti-tau vaccine, anti-tau monoclonal antibody, and anti-tau and anti-Abeta small molecules. “The potential of our platform to generate new molecules quickly is unlimited,” claims Dr. Pfeifer.

In the next year, AC Immune plans to test an anti-Abeta vaccine for Down syndrome, which causes early onset Alzheimer’s. Animal studies suggest that cognitive impairment in Down syndrome can be improved by targeting Abeta.

Misfolded Abeta and tau are involved in other diseases with few treatment options. AC Immune will leverage its therapeutic strategy for other conformational diseases of the central nervous system, says Dr. Pfeifer. By diversifying its pipeline, the company reduces risk and creates more value.

Readers' Comments

Posted 03/01/2013 by Daniel Quinn

Not sure about the Abeta programs. Too many failures already. Looks like the tau discovery efforts are the ones to watch. Heartily recommend that investors read 3000 days of dementia. AC Immune could be real buy op if crenezumab fails prior to any tau data coming out. This should (of course) not be taken as financial or investment advice of any kind :)

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